Interferons (IFNs) are a family of multifunctional cytokines with antiviral activities The K9 open reading frame of Kaposi's sarcoma-associated herpesvirus (KSHV) exhibits significant homology with cellular IFN regulatory factors (IRFs) We have investigated the functional consequence of K9 expression in IFN-mediated signal transduction Expression of K9 dramatically repressed transcriptional activation induced by IFN-`, - , and - Further, it induced transformation of NIH 3T3 cells, resulting in morphologic changes, focus formation, and growth in reduced-serum conditions The expression of antisense K9 in KSHV-infected BCBL-1 cells consistently increased IFN-mediated transcriptional activation but drastically decreased the expression of certain KSHV genes Thus, the K9 gene of KSHV encodes the first virus-encoded IRF (v-IRF) which functions as a repressor for cellular IFN-mediated signal transduction In addition, v-IRF likely plays an important role in regulatin g KS HV gene expression These results suggest that KSHV employs an unique mechanism to antagonize IFN-mediated antiviral activity by harboring a functional v-IRF PUBLICATIONS Li, M , Lee, H, Guo, J, Neipel, F, Fleckenstein, B, Ozato, K, and Jung, JU Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor J Virol 1998; 72:5433-5440